Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Identification of a RING protein that can interact in vivo with the BRCA1 gene product

Abstract

The hereditary breast and ovarian cancer gene, BRCA1, encodes a large polypeptide that contains the cysteine–rich RING motif, a zinc–binding domain found in a variety of regulatory proteins. Here we describe a novel protein that interacts in vivo with the N–terminal region of BRCA1. This BRCA1–associated RING domain (BARD1) protein contains an N–terminal RING motif, three tandem ankyrin repeats, and a C–terminal sequence with significant homology to the phylogenetically conserved BRCT domains that lie near the C terminus of BRCA1. The BARD1/BRCA1 interaction is disrupted by BRCA1 missense mutations that segregate with breast cancer susceptibility, indicating that BARD1 may be involved in mediating tumour suppression by BRCA1.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Hall, J.M. et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250, 1684–1689 (1990).

    Article  CAS  PubMed  Google Scholar 

  2. Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66–71 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Futreal, P.A. et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science 266, 120–122 (1994).

    Article  CAS  PubMed  Google Scholar 

  4. Castilla, L.H. et al. Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer. Nature Genet. 8, 387–391 (1994).

    Article  CAS  PubMed  Google Scholar 

  5. Simard, J. et al. Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. Nature Genet. 8, 392–398 (1994).

    Article  CAS  PubMed  Google Scholar 

  6. Friedman, L.S. et al. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nature Genet. 8, 399–404 (1994).

    Article  CAS  PubMed  Google Scholar 

  7. Easton, D.F., Bishop, D.T., Ford, D. & Crockford, G.P. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am. J. Hum. Genet. 52, 678–701 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Ford, D., Easton, D.F., Bishop, D.T., Narod, S.A. & Goldgar, D.E. Risks of cancer in BRCA1 -mutation carriers. Breast Cancer Linkage Consortium. Lancet 343, 692–695 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Saurin, A.J., Borden, K.L.B., Boddy, M.N. & Freemont, P.S. Does this have a familiar RING? Trends Biochem. Sci. 21, 208–214 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Bennett, M.L. et al. Isolation of the mouse homologue of BRCA1 and genetic mapping to mouse chromosome 11. Genomics 29, 576–581 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Lane, T.F. et al. Expression of Brca1 is associated with terminal differentiation of ectodermally and mesodermally derived tissues in mice. Genes Dev. 9, 2712–2722 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Sharan, S.K., Wims, M. & Bradley, A. Murine Brca1: sequence and significance for human missense mutations. Hum. Mot. Genet. 4, 2275–2278 (1995).

    Article  CAS  Google Scholar 

  13. Koonin, E.V., Altschul, S.F. & Bork, P. BRCA1 protein products: functional motifs. Nature Genet. 13, 266–267 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Fields, S. & Song, O. -k. A novel genetic system to detect protein–protein interactions. Nature 340, 245–246 (1989).

    Article  CAS  PubMed  Google Scholar 

  15. Chien, C.-t., Bartel, P.L., Sternglanz, R. & Fields, S. The two-hybrid system: A method to identify and clone genes for proteins that interact with a protein of interest. Proc. Natl. Acad. Sci. USA 88, 9578–9582 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Durfee, T. et al. The retinoblastoma protein associates with the protein phosphatase type 1 catalytic subunit. Genes Dev. 7, 555–569 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. Harper, J.W., Adami, G.R., Wei, N., Keyomarsi, K. & Elledge, S.J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75, 805–816 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Dang, C.V. et al. Intracellular leucine zipper interactions suggest c-Myc hetero-oligomerization. Mol. Cell. Biol. 11, 954–962 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hsu, H.-L., Wadman, I. & Baer, R. Formation of in vivo complexes between the TAL1 and E2A polypeptides of leukemic T cells. Proc. Natl. Acad. Sci. USA 91, 3181–3185 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tsan, J.T. et al. Mammalian cells as hosts for two-hybrid studies of protein–protein interaction. in The Yeast Two-hybrid System (eds. Bartel, P.L & Fields, S.) (Oxford University Press, Oxford, in the press).

  21. Hopp, T.P. et al. A short polypeptide marker sequence useful for recombinant protein identification and purification. BioTechnology 6, 1204–1210 (1988).

    Article  CAS  Google Scholar 

  22. Bork, P. Hundreds of ankyrin-like repeats in functionally diverse proteins: Mobile modules that cross phyla horizontally. Prot. Struct. Funct. Genet. 17, 363–374 (1993).

    Article  CAS  Google Scholar 

  23. Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).

    Article  CAS  PubMed  Google Scholar 

  24. Landschulz, W.H., Johnson, P.F. & McKnight, S.L. The leucine zipper: A hypothetical structure common to a new class of DNA binding proteins. Science 240, 1759–1764 (1988).

    Article  CAS  PubMed  Google Scholar 

  25. Murre, C., McCaw, P.S. & Baltimore, D. A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell 56, 777–783 (1989).

    Article  CAS  PubMed  Google Scholar 

  26. Sadowski, I., Bell, B., Broad, P. & Hollis, M. GAL4 fusion vectors for expression in yeast or mammalian cells. Gene 118, 137–141 (1992).

    Article  CAS  PubMed  Google Scholar 

  27. Andersson, S., Davis, D.N., Dahlback, H., Jornvall, H. & Russell, D.W., Cloning, structure, and expression of the mitochondrial cytochrome P-450 sterol 26-hydroxylase, a bile acid biosynthetic enzyme. J. Biol. Chem. 264, 8222–8229 (1989).

    CAS  PubMed  Google Scholar 

  28. Smith, D.B. & Johnson, K.S. Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. Gene 67, 31–40 (1988).

    Article  CAS  PubMed  Google Scholar 

  29. Guan, K. & Dixon, J.E. Eukaryotic proteins expressed in Escherichia coli: An improved thrombin cleavage and purification procedure of fusion proteins with glutathione S-transferase. Analyt. Biochem. 192, 262–267 (1991).

    Article  CAS  PubMed  Google Scholar 

  30. Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular cloning: a laboratory manual (Cold Spring Harbor Press, Cold Spring Harbor, New York, 1989).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Richard Baer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, L., Wang, Z., Tsan, J. et al. Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat Genet 14, 430–440 (1996). https://doi.org/10.1038/ng1296-430

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1296-430

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing